OVERVIEW

Benzodiazepines are sedating drugs, which do not usually cause either profound CNS or respiratory depression or any non-sedative effects. Deaths may occur prior to hospital due to sedation (particularly if combined with other sedative drugs e.g., alcohol) but the course of patients reaching hospital is generally uncomplicated. Zaleplon, zolpidem and zopiclone are not benzodiazepines but have similar toxicity in overdose and bind to the BZ1 receptor subtype of the benzodiazepine receptor adjacent to the GABA-A receptor in the central nervous system. Diazepam and many of the others are regularly abused. Street names for diazepam include: Benzo; Black pearl; Blue; Blue bombers; Blue boys; Blue magoos; Blue thunder; Blues; Drunk pills; La Roche; Ludes; Mother's little helper; Mother's little helpers; Pami; Roaches; Roachies; Roche; V; Vs blues; Valleys; Vallies; Vals.

Zolpidem
The GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex is not homogenous and can be assembled from multiple different combinations of alpha, beta and gamma sub-units. Zolpidem is a potent agonist at GABA(A) receptors but only those containing the alpha1 subunit (corresponding to the benzodiazepine (BZ)1 or omega1 subtype); it is not effective at receptors containing the alpha5 subunit (corresponding to one type of BZ2 or omega2 receptors). It is this selectivity for BZ1 receptors that is thought to explain its greater potency as a sedative-hypnotic and lesser activity as a muscle relaxant and anticonvulsant. The sedative-hypnotic effects are antagonised by flumazenil. It has been proposed that zolpidem lacks benzodiazepine-like side-effects, having minimal abuse and dependence potential. Nevertheless, there are a considerable number of zolpidem dependence case reports in the literature and a withdrawal syndrome including seizures exists. Zolpidem has recently been classified as a psychotropic at risk of abuse in Europe.

Zopiclone
Zopiclone is a potent agonist at binding sites that belong to the GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex but which are not the benzodiazepine specific sites. The GABA(A) receptor-benzodiazepine receptor-chloride ion channel complex is discussed in the benzodiazepine monograph. Zopiclone either acts on a site distinct from that of benzodiazepines or induces conformational changes different from those induced by benzodiazepines. It is possible that zopiclone acts via the mitochondrial benzodiazepine receptor which can result in allosteric modulation of GABA(A) receptor function. Zopiclone has no effect on other brain receptors such as the GABA receptor itself, dopamine receptors, serotonin or noradrenergic receptors. The sedative-hypnotic effects are antagonized by flumazenil. As with zolpidem, initial suggestions were that there was little or no potential for tolerance, abuse or dependence, however, it is clear that all can occur and that a withdrawal syndrome including delirium exists.

KINETICS IN OVERDOSE

Absorption

All benzodiazepines are lipid soluble drugs that are absorbed fairly rapidly. The rate of absorption is an important variable in determining the clinical effects of benzodiazepines. Rapid rises in serum concentrations lead to greater depth of sedation than slow rises to the same concentrations. The most rapidly absorbed drugs are temazepam and flurazepam and less rapidly absorbed drugs include oxazepam. The extent of absorption of these drugs is high.

Distribution

All these drugs are highly protein bound and have volumes of distributions of about 1 L/kg. They distribute well into the central nervous system.

Metabolism - Elimination

All benzodiazepines are hepatically metabolised with renal clearance accounting for less than 5%. The half-life of these drugs varies widely and a number of drugs have active metabolites. Drug with a shorter half-life (temazepam, triazolam) and drugs with a longer half-life (diazepam, clonazepam) still have very similar spectrums of clinical toxicity. This is due to the development of tolerance to the effects of benzodiazepines. It is actually the development of tolerance to the benzodiazepines that determines the recovery of consciousness rather than the clearance of the drug.

Zolpidem

After a single 20 mg oral dose peak plasma concentrations of 0.192 to 0.324 mg/L occur 0.75 to 2.6 hours post dose. Zolpidem was identified in the blood of 29 subjects arrested for impaired driving. Zolpidem concentrations ranged from 0.05 to 1.4 mg/L (mean 0.29 mg/L). In the subjects where zolpidem was present with other drugs and/or alcohol, symptoms reported included slow movements and reactions, slow and slurred speech, poor coordination, lack of balance, flaccid muscle tone, and horizontal and vertical gaze nystagmus. In five separate cases, where zolpidem was the only drug detected (0.08–1.40 mg/L, mean 0.65 mg/L), signs of impairment included slow and slurred speech, slow reflexes, disorientation, lack of balance and coordination, and “blacking out”. After ingestion of 300 mg of zolpidem, an initial plasma concentration of > 0.5 mg/L was reported in a comatose patient.

Zopiclone

The disposition of the enantiomers of zopiclone was investigated after oral administration of a single dose of 15 mg of a racemic mixture (twice the usual therapeutic dose) in 12 adult Caucasian volunteers. Determination of concentrations of zopiclone enantiomers in plasma showed that zopiclone pharmacokinetics is stereoselective with peak concentrations of 0.0873 and 0.044 mg/L for (+)-zopiclone and (-)-zopiclone, respectively.

After zopiclone 7.5 mg, alcohol enhanced and prolonged the effects without modifying plasma concentration. After oral ingestion of 300 mg of zopiclone, the plasma concentration was 1.6 mg/L at 4.5 hours after the dose and the elimination half-life was 3.5 hours.

CLINICAL EFFECTS

The clinical effects of benzodiazepine poisoning are due entirely to central nervous system depression. Severe poisonings may develop hypothermia, bradycardia, and hypotension, however this is unusual. Respiratory depression and depression of consciousness may lead to aspiration pneumonia. However, deep coma is unusual. Most patients are stuporous or still responsive to painful stimuli unless they have co-ingested other sedating drugs.

Zolpidem
Zolpidem in overdose generally produces mild CNS depression with drowsiness, slow movements and reactions, slow and slurred speech, poor coordination, lack of balance, flaccid muscle tone, and horizontal and vertical gaze nystagmus. Occasionally more severe CNS depression occurs with development of a profound but short-lasting coma, associated with pin-point pupils and respiratory depression especially if other drugs or ethanol are ingested or in cases of chronic hepatic or respiratory insufficiency. Pulmonary oedema occurs in fatal cases.
In a large series of 244 cases of intentional acute overdoses, half of the patients ingested other substances (psychotropic drugs and alcohol) concomitantly. Signs of intoxication were observed in two thirds of the population but could be attributed to zolpidem in only 105 cases with drowsiness, vomiting, coma or respiratory failure. There were no electrocardiographic abnormalities that appeared to be directly related to zolpidem and symptoms of intoxication rapidly remitted in 91% of cases.
In a series of 91 well documented cases of acute zolpidem intoxication there were 54 single-drug poisonings with zolpidem. Of these, only one patient became comatose. On the other hand, in combined intoxications with other CNS active drugs or ethanol, coma was more common even if the amount of the additionally ingested drugs in itself would not have caused a comatose state.
In a series of 12 pediatric zolpidem exposures, in ten cases onset of symptoms was within 10 to 60 min (mean 31.6 min). The duration of symptoms in the unintentional cases ranged from less than 60 min up to 4 hours (mean 2.4 hours) and 6–10 hours (mean 7.5 hours) in the intentional exposures.

Zopiclone
Drowsiness, lethargy and ataxia are the principal effects reported in zopiclone overdose. Rarely, coma may occur. In a death due to respiratory failure after zopiclone overdose it was postulated that hypoventilation due CNS depression occurred. Similar to benzodiazepines, coma may be due to flow limitation and obstructive apnoea via an increase in upper airway resistance and work of breathing. There is a single case report of first-degree heart block after zopiclone poisoning.

DIFFERENCES IN TOXICITY

Rapidly absorbed drugs lead to greater degrees of CNS depression than slowly absorbed drugs. There are differences in fatal toxicity within this class with temazepam and flurazepam having much higher rates of fatal overdose per prescription than other drugs such as oxazepam. This appears to be due to sedation as temazepam has been found more sedating in overdose than oxazepam. However, in a patient who presents with benzodiazepine overdose, these differences do not require any change to management. Zaleplon, zolpidem and zopiclone are not benzodiazepines but have similar toxicity in overdose and bind to the BZ1 receptor subtype of the benzodiazepine receptor adjacent to the GABA-A receptor in the central nervous system.

Zolpidem
Zolpidem, in therapeutic doses, has been implicated in psychotic reactions characterized by auditory and visual hallucinations as well as delusional thinking. In a large series (344 cases) of zolpidem overdose in adults, ingested doses of zolpidem ranged between 10 and 1400 mg. Drowsiness occurred at doses of 140 to 440 mg; coma or respiratory failure were rare. In a series of 54 single-drug poisonings with zolpidem in adults, only mild symptoms were observed up to 600 mg. Patients mainly suffered from somnolence. Only one patient became comatose after ingestion of 600 mg zolpidem. On the other hand, in combined intoxications with other CNS active drugs or ethanol a zolpidem dose as low as 100–150 mg induced coma in some patients, even if the amount of the additionally ingested drugs in itself would not have caused a comatose state. In a 44-year old male an overdose of 200 mg of zolpidem alone resulted in coma (GCS of 7) and respiratory failure. In a series of 12 pediatric ingestions, one child had no effect with 2.5 mg. As little as 5 mg caused symptoms with minor outcome in six unintentional ingestions (5–30 mg). Minor to moderate symptoms were reported 1–4 hours after intentional ingestions (12.5–150 mg).

Zopiclone
After a therapeutic dose of zopiclone (7.5 mg), alcohol enhanced and prolonged the effect without modifying plasma concentrations.
Transient first degree AV heart block occurred after ingestion of 127.5 mg of zopiclone (in combination with piperazine). Sleepiness was the only feature after an oral ingestion of 300 mg of the drug.
A 72-year-old man being treated for lung cancer ingested 90 mg of zopiclone in a suicide attempt and died between 4 and 10 hours after the ingestion. A combined ingestion of alcohol and 150 mg of zopiclone resulted in the death of a 29-year old woman. A 72-year-old woman with poor respiratory function due to bronchogenic carcinoma died after ingesting 200 to 350 mg of zopiclone.

TREATMENT

The preferred treatment is entirely supportive with maintenance of the airway and ventilation, IV access and fluids.

GI Decontamination

Oral activated charcoal is of no value in pure benzodiazepine poisoning. It may be given to patients who have recently (within 1 hour) ingested benzodiazepines with other drugs that may benefit from decontamination. Gastric lavage is not indicated.

Flumazenil

Flumazenil is a benzodiazepine antagonist. It may be used for either diagnosis or treatment. It also is effective for zaleplon, zolpidem and zopiclone. However, patients are likely to wake from their sedation or coma because of the rapid development of tolerance rather than from clearance of the drug. The administration of a benzodiazepine antagonist such as flumazenil in the presence of a benzodiazepine prevents of the development of tolerance. This could theoretically result in a prolongation of the effect of the benzodiazepine manifesting as a prolonged requirement for the antagonist and hospital length of stay. This has been seen after diazepam overdose treated with flumazenil while, in contrast, a much shorter duration of symptoms was seen with similar doses managed before the availability of an antagonist. For routine management of uncomplicated benzodiazepine, zaleplon, zolpidem or zopiclone overdose there is no indication for the use of flumazenil.

Diagnostic use

Flumazenil (0.1–2.0 mg IV) has been given to unconscious patients where the drug ingested is unknown although this remains controversial. Flumazenil should only be given if there is no evidence of proconvulsant/proarrhythmic drug ingestion as the removal of the effects of benzodiazepines or other similar drugs that have been co-ingested may lead to seizures, cardiac arrest or death.

Contraindications to flumazenil administration

Indications that the patient may have ingested proconvulsant drug include:

widened QRS complex on the ECG

hyperreflexia and myoclonus

anticholinergic signs

marked tachycardia

hypokalaemia

Elimination enhancement

This is not indicated.

LATE COMPLICATIONS

Long term sequelae are unusual and patients usually recover consciousness within twelve hours although the elderly may take considerably longer. Patients who fail to regain consciousness within this time should have a search made for alternative causes of sedation including non-toxicological causes.
Patients with a significant sedative drug overdose should be advised not to drive until potential interference with psychomotor performance has resolved. For overdose of most of these agents this will be at least 48–72 hours after discharge.